1. Field of the Invention
The present invention relates to a process for preparing thiophene derivatives and novel compounds obtained thereby and in more detail, this invention relates to a process for preparing a series of thiophene derivatives, from which 2-thiopheneacetic acids having or not having substituent or esters thereof can easily be prepared, in high yields and selectivity by using substituted or unsubstituted thiophenes as the starting materials by easy operations and novel compounds, i.e. .alpha.-arylthio-2-thiopheneacetic acids having or not having substituent or esters thereof, obtained in the course of the process.
2. Description of the Prior Art
Prior to the invention, it was known that the compounds represented by the general formula ##STR1## (wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, halogen or lower alkyl group and X is chlorine or bromine) can be, for example, converted to useful insecticides structurally analogous to DDT by condensation with other aromatic compounds (e.g., H. D. Hartough, "The Chemistry of Heterocyclic Compounds"--Thiophene and its Derivatives, Interscience Publishers, Inc., New York, 1952, p. 189), and the carboxylates of the compounds with the general formula (I) themselves are reported to show insecticidal activities (R. C. Blinn et al., J. Amer. Chem. Soc., 76, 37 (1954)).
The process for the preparation of .alpha.-trihalomethyl-2-thiophenemethanols heretofore known to the art comprises the preparation of the Grignard reagent from a 2-bromothiophene and magnesium and then reacting the said reagent with trichloroacetaldehyde to give an .alpha.-trihalomethyl-2-thiophenemethanol (J. Amer. Chem. Soc., 71, 2859 (1949)). However, this process cannot be adopted commercially because of the difficulty in the selective synthesis of the starting material, i.e. 2-bromothiophene, and because the process disadvantageously requires an anhydrous condition and necessitates the use of flammable ethers as the reaction medium when preparing the Grignard reagent.
Also, processes for the preparation of .alpha.-substituted 2-thiopheneacetic acid derivatives having the general formula ##STR2## (wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, halogen or lower alkyl group and R.sup.3 is alkoxy group, hydroxyl group or amino group) heretofore known to the art are: (1) the condensation of a 2-thiophenealdehyde with bromoform in the presence of a base (J. Amer. Chem. Soc., 83, 2755 (1961)), (2) the oxidation of a 2-acetylthiophene with selenium dioxide and then treating with an alkali (Arkiv Kemi., 11, 519 (1957)), (3) the preparation of 2-thiophenealdehyde cyanohydrin and then conducting hydrolysis (Japanese Patent Disclosure No. 8775/73), (4) the addition of glyoxylic acid on thiophene (Japanese Patent Disclosure No. 49954/74), etc.
However, the process (1) necessitates the use of expensive bromoform and 2-thiophenealdehyde as the raw materials and the yield of the product is low. The process (2) necessitates the use of expensive and dangerous selenium dioxide and is difficult to adopt as a commercial process. The process (3) requires 2-thiophenealdehyde which is difficultly accessible commercially, and necessitates the use of highly poisonous hydrogen cyanide. Although the process (4) requires a shorter reaction step, yield of the product is low and is thus difficult to adopt as a commercial process.
Further, the process for the preparation of 2-thiopheneglycolic acid by the reduction of 2-thiopheneglyoxylic acid in an alcohol by the use of sodium amalgam was known prior to the invention (F. Ernst, Ber., 19, 3278 (1886)), however, commercial production by the process above is difficult, since the prior synthetic method gives 2-thiopheneglyoxylic acid in relatively low yield, which is required as the starting material.
It was known that the .alpha.-substituted 2-thiopheneacetic acid derivatives themselves can be converted to penicillin derivatives having antibiotical activities by reacting them with penicillanic acid derivatives (Cf. e.g. Netherlands Octrooiaanvrage No. 6506584), and 2-thiopheneacetic acids which are the compounds obtainable by replacing the substituent located in .alpha.-position of said .alpha.-substituted 2-thiopheneacetic acids with hydrogen are very useful as chemical modifier of penicillin and cephalosporin (Cf. J. Amer. Chem. Soc., 84, 3401 (1962)).
The main processes for the preparation of 2-thiopheneacetic acid heretofore known may be classified into three processes described below, according to the starting materials employed: (1) converting 2-chloromethylthiophene to 2-cyanomethylthiophene at first by treating with an alkali cyanide, and then conducting hydrolysis thereof (Japanese Patent Disclosure No. 46063/77); (2) converting by Willgerodt reaction of 2-acetylthiophene with ammonium polysulfide to 2-thiopheneacetamide at first and then conducting hydrolysis thereof (Otto Dann, Ger. Pat. No. 832755 (1952)), (3) (a) reacting potassium cyanide and an ester of chloroformic acid on 2-thiophenealdehyde to form an .alpha.-alkoxycarbonyloxy-2-thiopheneacetonitrile, and then conducting catalytic hydrogenation thereof to 2-cyanomethylthiophene, and further conducting hydrolysis thereof (M. J. Soulal, M. C. Woodford, British Pat. No. 1,122,658 (1968); (b) treating the condensation product of 2-thiophenealdehyde and methyl methylthiomethyl sulfoxide with hydrogen chloride in alcohol to form an ester of 2-thiopheneacetic acid and then conducting hydrolysis thereof (Japanese Patent Disclosure No. 46063/77); etc. However, the process (1) includes difficulties in that 2-chloromethylthiophene is difficult to handle because it is unstable, explosive, and is a lachrymatory substance, and also, highly poisonous bis(chloromethyl) ether is formed as by-product during the preparation of this compound. The process (2) possesses shortcomings in that it requires a high-temperature and high-pressure condition in performing the Willgerodt reaction, and requires severe conditions for the hydrolysis. Also, the process (3) (a) has its demerit in that it necessitates the use of highly poisonous cyanide compounds, and requires many reaction stages, etc. The process (3) (b) in disadvantageous in that it needs attention in handling, and produces sulfur compounds having strong unpleasant odor.